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First, will this combination benefit patients with heart failure who are unlike the patients enrolled in this trial?

Second, if and when the combination is approved, how will patients and doctors decide to give it a try?

Third, will the sponsor share the raw data so that others can carefully assess the findings?

About that last question, he wrote:

“The published article states that the sponsor, Novartis, collected, managed, and analyzed the data. The article states that the analysis followed a pre-specified plan and that an independent academic statistician replicated the analyses. However, it is not clear whether that person had access to all the raw data and forms and to what extent the statistician could assess what was done by the company. There is no reason to suspect that there is a problem and the trial did have academic stars leading it and involved in many phases of it. Nevertheless, this trial has the potential to produce a multi-billion dollar revenue stream to the company that conducted the study – and for that reason it would seem prudent to provide the opportunity for thorough replication with all the raw data by one or more independent groups. Regulatory agencies will see the data – but it would be better if there were an opportunity for independent replication by other scientists. If companies are going to run the studies that evaluate their products, then transparency is even more important than in other circumstances.”

“The response to PARADIGM-HF has been positive partly because it has been a long time any new drug has been shown to improve mortality in patients with HF. But our desire to find better options for these patients does not mean we should lower the standards for what counts as a good trial. Few providers would consider a randomized trial comparing valsartan at 320 mg with enalapril at 20 mg to be fair — and adding a novel drug to the valsartan does not make this comparison more palatable. Instead, PARADIGM HF shows that with a large number of patients and the “right” trial design, you can get any conclusion you want. As William Randolph Hearst said, “You furnish the pictures, and I’ll furnish the war.”

PARADIGM-HF does convince me that more angiotensin-pathway blockade is better, but it does not prove the benefit of a novel drug. A history of negative HF trials should teach us that the pretest probability that a novel drug works is very low in HF. The data from PARADIGM-HF do not greatly alter the probability that the drug works.

The concerns I have highlighted cannot be remedied, even with full access to the study data (which should nevertheless be made available) — instead, they are hard-wired into the trial design. For that reason, we must ask for another randomized trial — one that is truly done right. Heart failure patients deserve no less.”

“Unfortunately, the clinical trial that just generated much favorable publicity ahead of regulatory consideration of this drug had major, possibly fatal flaws. … Study results may not generalize to many real-life patients. There are reasons to be concerned about whether the quality of study implementation was adequate. … Therefore, all the enthusiasm about this drug may be premature, and does not appear to be evidence-based”

“This has been hyped as the biggest breakthrough in heart failure for at least 20 years. … this trial is a perfect example of everything that is wrong with heart failure trials. The mean age of the 8442 patients was 63.8, nearly 80% were male, and they were selected by reduced ejection fraction in 1043 centres across 47 countries. A logistic nightmare, but a great way for Novartis to spread influence. And Novartis then collected, managed and analyzed all the data itself. As I have said, a submaximal dose of one drug was compared with a maximal dose of another plus an extra ingredient. There was a run-in period, in which patients who were intolerant to the new treatment (12%) dropped out. Adding bias to bias, the trial was terminated prematurely. … As I draw to the end of a clinical career in which I’ve tried to help people with heart failure, I stand bemused. This is just how things have been done for the last 30 years, and it’s not good enough.”

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